:Cathinone

Khat has been cultivated in the Horn of Africa and Arabian Peninsula region of the world for thousands of years. It is most commonly chewed for the euphoric effect it produces. The active ingredient was first proposed in 1930, when cathine was identified as a predominant alkaloid in the plant.{{cite journal | vauthors = Patel NB | title = Mechanism of action of cathinone: the active ingredient of khat (Catha edulis) | journal = East African Medical Journal | volume = 77 | issue = 6 | pages = 329–332 | date = June 2000 | pmid = 12858935 | doi = 10.4314/eamj.v77i6.46651 | doi-access = free }} Cathine was thought to be the main active ingredient in khat until the 1960s, when it was found that the amount of cathine in the khat leaves is insufficient to produce the effects observed. In 1975, the United Nations Narcotic Laboratory analyzed khat leaves from Yemen, Kenya and Madagascar and found evidence of a different alkaloid, cathinone. Cathinone is molecularly similar to cathine, but is much more abundant in younger plants. This finding caused scientists to speculate that cathinone was the true active ingredient in khat.

A study was conducted in 1994 to test the effects of cathinone. Six volunteers who had never chewed khat were given an active khat sample and a cathinone-free placebo sample.{{cite journal | vauthors = Widler P, Mathys K, Brenneisen R, Kalix P, Fisch HU | title = Pharmacodynamics and pharmacokinetics of khat: a controlled study | journal = Clinical Pharmacology and Therapeutics | volume = 55 | issue = 5 | pages = 556–562 | date = May 1994 | pmid = 7910126 | doi = 10.1038/clpt.1994.69 | s2cid = 25788465 }} The researchers analyzed the participants' moods, activity levels and blood pressure before and after consuming the khat or placebo. This analysis showed that cathinone produced amphetamine-like effects, leading the researchers to confirm that cathinone, not cathine, is the active ingredient in khat leaves.

File:Qat man.jpg

Over 20 million people in the Arabian Peninsula and East Africa chew khat leaves daily. It is an important piece of the culture and economy in this region, especially in Ethiopia (where khat is said to have originated), Kenya, Djibouti, Somalia and Yemen. Men usually chew it during parties or other social gatherings while smoking cigarettes and drinking tea. Farmers and other workers also use khat in the afternoon to reduce fatigue and hunger as the day goes on. It functions like the caffeine in a strong cup of coffee as an anti-fatigue drug. Students and drivers have been known to use it to stay alert for longer periods of time.{{cite news| vauthors = Kirby A |title=Yemen's khat habit soaks up water |url=http://news.bbc.co.uk/2/hi/programmes/from_our_own_correspondent/6530453.stm |website=BBC News|date=7 April 2007|publisher=BBC|access-date=20 March 2015|url-status=live|archive-url= https://web.archive.org/web/20141012084142/http://news.bbc.co.uk/2/hi/programmes/from_our_own_correspondent/6530453.stm|archive-date=12 October 2014}}

In order to produce its desired effects, khat leaves should be chewed fresh. The fresh leaves have a higher concentration of cathinone. Waiting too long after cultivation to chew the leaf will allow the cathinone to break down into its less potent form, cathine. Because of the need for quick chewing, it is a habit that has historically been prevalent only where the plant grows. However, in the recent years with improvements in road and air transport, khat chewing has spread to all corners of the world.

The cultivation of khat in Yemen is a highly profitable industry for farmers. Khat plants will grow differently depending on the climate they are grown in and each one will produce different amounts of cathinone.{{cite journal | vauthors = Al-Motarreb A, Baker K, Broadley KJ | title = Khat: pharmacological and medical aspects and its social use in Yemen | journal = Phytotherapy Research | volume = 16 | issue = 5 | pages = 403–413 | date = August 2002 | pmid = 12203257 | doi = 10.1002/ptr.1106 | s2cid = 9749292 }} It generally grows best in coastal, hot climates. In Yemen, the khat plant is named after the region in which it is grown. The Nehmi khat plant has the highest known concentration of cathinone, 342.5 mg/100 g.

Internationally, cathinone is a Schedule I drug under the Convention on Psychotropic Substances.{{cite web | url = http://www.incb.org/pdf/e/list/green.pdf | archive-url = https://web.archive.org/web/20120831222336/http://www.incb.org/pdf/e/list/green.pdf | archive-date = 2012-08-31 | title = List of psychotropic substances under international control | work = International Narcotics Control Board | publisher = United Nations | year = 2003 }} Circa 1993, the DEA added cathinone to the Controlled Substances Act's Schedule I.

The sale of khat is legal in some jurisdictions, but illegal in others (see Khat (Regulation)). Substituted cathinones were also often used as the key ingredient of recreational drug mixes commonly known as "bath salts" in the United States.{{cite news |url=https://www.pbs.org/newshour/bb/science/july-dec12/bathsalts_09-20.html | archive-url = https://web.archive.org/web/20121229055853/https://www.pbs.org/newshour/bb/science/july-dec12/bathsalts_09-20.html | archive-date = 29 December 2012 |title=Synthetic Street Drug Camouflaged as Bath Salts Has Dangerous, Bizarre Effects |publisher=PBS NewsHour |date=20 September 2012 |access-date=7 December 2013 |url-status=dead }}{{cite web| vauthors = Urquhart C | date = 4 September 2004 | work = The Guardian | url = https://www.theguardian.com/world/2004/sep/04/Israel | title = Drugs and dance as Israelis blot out intifada | archive-url = https://web.archive.org/web/20161108053442/https://www.theguardian.com/world/2004/sep/04/israel | archive-date = 8 November 2016 | access-date = 19 April 2015 }}{{cite web | vauthors = Chai C | date = 16 April 2015 | work = Globalnews.ca | url = http://globalnews.ca/news/1942263/what-you-need-to-know-about-flakka-the-latest-drug-causing-erratic-behaviour/ | title = What you need to know about flakka, the latest drug causing erratic behaviour | archive-url = https://web.archive.org/web/20150420001955/http://globalnews.ca/news/1942263/what-you-need-to-know-about-flakka-the-latest-drug-causing-erratic-behaviour/ | archive-date = 20 April 2015 | access-date = 19 April 2015 }}{{cite web |vauthors=Extance A |title=The rising tide of 'legal highs' |url=https://www.chemistryworld.com/feature/the-rising-tide-of-legal-highs/3007738.article |website=Chemistry World |access-date=3 August 2018 |language=en |archive-date=3 August 2018 |archive-url=https://web.archive.org/web/20180803224149/https://www.chemistryworld.com/feature/the-rising-tide-of-legal-highs/3007738.article |url-status=live }}

The table below shows the legality of khat and cathinone in various countries:

Cathinone has been found to stimulate the release of dopamine and inhibit the reuptake of epinephrine, norepinephrine and serotonin in the central nervous system (CNS). These neurotransmitters are all considered monoamines and share the general structure of an aromatic ring and an amine group attached by a two-carbon separator. Because cathinone is a hydrophobic molecule, it can easily cross cell membranes and other barriers, including the blood–brain barrier. This property allows it to interact with the monoamine transporters in the synaptic cleft between neurons. Cathinone induces the release of dopamine from brain striatal preparations that are prelabelled either with dopamine or its precursors.{{cite journal | vauthors = Kalix P | title = Cathinone, an alkaloid from khat leaves with an amphetamine-like releasing effect | journal = Psychopharmacology | volume = 74 | issue = 3 | pages = 269–270 | year = 1981 | pmid = 6791236 | doi = 10.1007/BF00427108 | s2cid = 20621923 }} It is more specifically a norepinephrine–dopamine releasing agent (NDRA) similarly to amphetamine.

The metabolites of cathinone, cathine and norephedrine, also possess CNS stimulation, but create much weaker effects.{{cite web|title=Cathinone|url=http://www.drugbank.ca/drugs/DB01560|website=Drug Bank|access-date=10 March 2015|url-status=live|archive-url=https://web.archive.org/web/20150423165202/http://www.drugbank.ca/drugs/DB01560|archive-date=23 April 2015}} The effects of cathinone on the body can be countered by a preceding administration of a dopamine receptor antagonist. The antagonist prevents synaptic dopamine released by cathinone from exerting its effect by binding to dopamine receptors.

Cathinone can also affect cholinergic concentrations in the gut and airways by blocking prejunctional adrenergic receptors (α₂ adrenergic) and activating 5-HT7 receptors, thereby inhibiting smooth muscle contraction.{{cite web| vauthors = Hugins KB |title=Cathinone: History, Synthesis, and Human Applications|url=http://www.slideshare.net/KevinHugins/cathinone-history-synthesis-and-human-applications|website=slideshare|date=17 July 2014|access-date=8 March 2015|url-status=live|archive-url=https://web.archive.org/web/20150704030825/http://www.slideshare.net/KevinHugins/cathinone-history-synthesis-and-human-applications|archive-date=4 July 2015}} It can also induce dry mouth, blurred vision and increased blood pressure and heart rate.

Cathinone is a weak agonist of the mouse, rat, and human trace amine-associated receptor 1 (TAAR1).{{cite journal | vauthors = Gainetdinov RR, Hoener MC, Berry MD | title = Trace Amines and Their Receptors | journal = Pharmacol Rev | volume = 70 | issue = 3 | pages = 549–620 | date = July 2018 | pmid = 29941461 | doi = 10.1124/pr.117.015305 | url = | doi-access = free }}{{cite journal | vauthors = Simmler LD, Buchy D, Chaboz S, Hoener MC, Liechti ME | title = In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1 | journal = J Pharmacol Exp Ther | volume = 357 | issue = 1 | pages = 134–144 | date = April 2016 | pmid = 26791601 | doi = 10.1124/jpet.115.229765 | url = https://web.archive.org/web/20250509235235/https://d1wqtxts1xzle7.cloudfront.net/74120533/eae6c6e62565b82d46b4d111bbea0f77b9c2-libre.pdf?1635931703=&response-content-disposition=inline%3B+filename%3DIn_Vitro_Characterization_of_Psychoactiv.pdf&Expires=1746838268&Signature=Sy4fJ90yUhxs68314NxYsW5PAaNrBGePRu35WRR4PIF-3YC7Z~sLdnCn5wfqqbLg9bDEGdt~oW55ugMP3D3jgA0BoRI~~GOb0NQOwrtfUEQK1PQs1uuN9qg5Y1ct8z5NsABm44RgtukkwRMdU6fO7OlfIsQ68hOiFk129Ll7UYqldxD2f1xhE2fTTfsxSpb8cMCJzHn7-ItqLdwnAUPFK7WggDIjmY1kCnaHLwIxMwdJCAq8L6DYzSTg7pZkbR8qlou~GXbTPQt~gYpyZTJp5hgW-7V6K5wLlQ7Z2xE7B0f9wEfuc1W1QNafg125Tr-vvAe4LEGKXV58bnn1bpfWKw__&Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA}} In contrast to cathinone however, most other cathinones are not human TAAR1 agonists.{{cite journal | vauthors = Kuropka P, Zawadzki M, Szpot P | title = A narrative review of the neuropharmacology of synthetic cathinones-Popular alternatives to classical drugs of abuse | journal = Hum Psychopharmacol | volume = 38 | issue = 3 | pages = e2866 | date = May 2023 | pmid = 36866677 | doi = 10.1002/hup.2866 | url = | quote = Another feature that distinguishes [synthetic cathinones (SCs)] from amphetamines is their negligible interaction with the trace amine associated receptor 1 (TAAR1). Activation of this receptor reduces the activity of dopaminergic neurones, thereby reducing psychostimulatory effects and addictive potential (Miller, 2011; Simmler et al., 2016). Amphetamines are potent agonists of this receptor, making them likely to self‐inhibit their stimulating effects. In contrast, SCs show negligible activity towards TAAR1 (Kolaczynska et al., 2021; Rickli et al., 2015; Simmler et al., 2014, 2016). [...] It is worth noting, however, that for TAAR1 there is considerable species variability in its interaction with ligands, and it is possible that the in vitro activity of [rodent TAAR1 agonists] may not translate into activity in the human body (Simmler et al., 2016). The lack of self‐regulation by TAAR1 may partly explain the higher addictive potential of SCs compared to amphetamines (Miller, 2011; Simmler et al., 2013). }} TAAR1 activation may auto-inhibit and constrain the monoaminergic effects of monoamine releasing agents possessing TAAR1 agonism.{{cite book | vauthors = Espinoza S, Gainetdinov RR | title=Taste and Smell | chapter=Neuronal Functions and Emerging Pharmacology of TAAR1 | series=Topics in Medicinal Chemistry | publisher=Springer International Publishing | publication-place=Cham | volume=23 | date=2014 | isbn=978-3-319-48925-4 | doi=10.1007/7355_2014_78 | pages=175–194 | quote = Interestingly, the concentrations of amphetamine found to be necessary to activate TAAR1 are in line with what was found in drug abusers [3, 51, 52]. Thus, it is likely that some of the effects produced by amphetamines could be mediated by TAAR1. Indeed, in a study in mice, MDMA effects were found to be mediated in part by TAAR1, in a sense that MDMA auto-inhibits its neurochemical and functional actions [46]. Based on this and other studies (see other section), it has been suggested that TAAR1 could play a role in reward mechanisms and that amphetamine activity on TAAR1 counteracts their known behavioral and neurochemical effects mediated via dopamine neurotransmission. }}

Khat leaves are removed from the plant stalk and are kept in a ball in the cheek and chewed. Chewing releases juices from the leaves, which include the alkaloid cathinone. The absorption of cathinone has two phases: one in the buccal mucosa and one in the stomach and small intestine. The stomach and small intestine are very important in the absorption of ingested alkaloids. At approximately 2.3 hours after chewing khat leaves, the maximum concentration of cathinone in blood plasma is reached. The mean residence time is 5.2 ± 3.4 hours. The elimination half-life of cathinone is 1.5 ± 0.8 hours. A two-compartment model for absorption and elimination best describes this data. However, at most, only 7% of the ingested cathinone is recovered in the urine. This indicates that the cathinone is being broken down in the body. Cathinone has been shown to selectively metabolize into R,S-(-)-norephedrine and cathine. The reduction of the ketone group in cathinone will produce cathine. This reduction is catalyzed by enzymes in the liver. The spontaneous breakdown of cathinone is the reason it must be chewed fresh after cultivation.

The first documentation of the khat plant being used in medicine was in a book published by an Arabian physician in the 10th century. It was used as an antidepressant because it led to feelings of happiness and excitement. Chronic khat chewing can also create drug dependence, as shown by animal studies. In such studies, monkeys were trained to push a lever to receive the drug reward. As the monkeys' dependence increased, they pressed the lever at an increasing frequency.

Khat chewing and the effects of cathinone on the body differ from person to person, but there is a general pattern of behavior that emerges after ingesting fresh cathinone:

1. Feelings of euphoria that last for one to two hours
2. Discussion of serious issues and increased irritability
3. Very active imagination
4. Depression
5. Irritability, loss of appetite and insomnia

There are other effects not related to the CNS. The chewer can develop constipation and heartburn after a khat session. Long-term effects of cathinone can include gum disease or oral cancer, cardiovascular disease and depression. The withdrawal symptoms of cathinone include hot flashes, lethargy and a great urge to use the drug for at least the first two days.

File:Non-Beta Oxidative Biosynthesis of Cathinone.png

The synthesis of cathinone in khat begins with L-phenylalanine and the first step is carried out by L-phenylalanine ammonia lyase (PAL), which cleaves off an ammonia group and creates a carbon-carbon double bond, forming cinnamic acid. After this, the molecule can either go through a beta-oxidative pathway or a non-beta-oxidative pathway. The beta-oxidative pathway produces benzoyl-CoA while the non-beta-oxidative pathway produces benzoic acid. Both of these molecules can be converted to 1-phenylpropane-1,2-dione by a condensation reaction catalyzed by a ThDP-dependent enzyme (Thiamine diphosphate-dependent enzyme) with pyruvate and producing CO₂. 1-phenylpropane-1,2-dione goes through a transaminase reaction to replace a ketone with an ammonia group to form (S)-cathinone. (S)-Cathinone can then undergo a reduction reaction to produce the less potent but structurally similar cathine or norephedrine, which are also found in the plant.{{cite journal | vauthors = Hagel JM, Krizevski R, Kilpatrick K, Sitrit Y, Marsolais F, Lewinsohn E, Facchini PJ | title = Expressed sequence tag analysis of khat (Catha edulis) provides a putative molecular biochemical basis for the biosynthesis of phenylpropylamino alkaloids | journal = Genetics and Molecular Biology | volume = 34 | issue = 4 | pages = 640–646 | date = October 2011 | pmid = 22215969 | pmc = 3229120 | doi = 10.1590/S1415-47572011000400017 }}

Aside from the beta- and non-beta-oxidative pathways, the biosynthesis of cathinone can proceed through a CoA-dependent pathway. The CoA-dependent pathway is actually a mix between the two main pathways as it starts like the beta-oxidative pathway and then when it loses CoA, it finishes the synthesis in the non-beta-oxidative pathway. In this pathway, the trans-cinnamic acid produced from L-phenylalanine is ligated to a Coenzyme A (CoA), just like the beginning of the beta-oxidative pathway. It then undergoes hydration at the double bond. This product then loses the CoA to produce benzaldehyde, an intermediate of the non-beta-oxidative pathway. Benzaldehyde is converted into benzoic acid and proceeds through the rest of the synthesis.

{{multiple image

| width = 300

| footer = Two mechanism of synthesizing Cathinone

| image1 = Synthesis of Enantiomerically Pure S-Cathinone.png

| alt1 = Synthesize enantiomerically pure S-Cathinone

| caption1 = Synthesize enantiomerically pure S-Cathinone

| image2 = Cathinone synthesis.svg

| alt2 = Racemic cathinone from propiophenone via the α-brominated intermediate

| caption2 = Racemic cathinone from propiophenone via the α-brominated intermediate

}}

Cathinone can be synthetically produced from propiophenone through a Friedel-Crafts acylation of propionic acid and benzene. The resulting propiophenone can be brominated, and the bromine can be substituted with ammonia to produce a racemic mixture of cathinone. A different synthetic strategy must be employed to produce enantiomerically pure (S)-cathinone. This synthetic route starts out with the N-acetylation of the optically active amino acid, S-alanine. Then, phosphorus pentachloride (PCl₅) is used to chlorinate the carboxylic acid forming an acyl chloride. At the same time, a Friedel-Crafts acylation is preformed on benzene with aluminum chloride catalyst. Finally, the acetyl protecting group is removed by heating with hydrochloric acid to form enantiomerically pure S-(-)-cathinone.

File:Bupropion skeletal.svg

Cathinone can be extracted from Catha edulis (khat), or synthesized from α-bromopropiophenone (which is easily made from propiophenone). Because cathinone is both a primary amine and a ketone, it is very prone to dimerization, especially as a free base isolated from plant matter.{{cite journal | vauthors = Oeri HE | title = Beyond ecstasy: Alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy | journal = J Psychopharmacol | volume = 35 | issue = 5 | pages = 512–536 | date = May 2021 | pmid = 32909493 | pmc = 8155739 | doi = 10.1177/0269881120920420 | url = }}{{cite web| vauthors = Shulgin A |title=4-Hydroxy-5-methoxy-N,N-dimethyltryptamine, Psilocybe mushrooms, Psilocin|url=http://www.cognitiveliberty.org/shulgin/blg/2005/12/4-hydroxy-5-methoxy-nn_07.html|date=7 December 2005|work=Ask Dr. Shulgin Online|access-date=10 September 2013|url-status=live|archive-url=https://web.archive.org/web/20130907234431/http://www.cognitiveliberty.org/shulgin/blg/2005/12/4-hydroxy-5-methoxy-nn_07.html|archive-date=7 September 2013}} These dimers are pharmacologically inactive, and the rapid dimerization reduces active amounts of cathinone in non-fresh khat. The rapid formation of dimers also applies to other non-N-substituted cathinones such as methylenedioxycathinone (MDC; normethylone).

The structure of cathinone is very similar to that of other molecules. By reducing the ketone, it becomes cathine if it retains its stereochemistry, or norephedrine if its stereochemistry is inverted. Cathine is a less potent version of cathinone and cathinone's spontaneous reduction is the reason that older khat plants are not as stimulating as younger ones. Cathinone and amphetamine are closely related in that amphetamine is only lacking the ketone C=O group.{{cite web|title=Synthetic cathinones drug profile|url=http://www.emcdda.europa.eu/publications/drug-profiles/synthetic-cathinones|website=European Monitoring Center for Drugs and Drug Addiction|publisher=EMCDDA|access-date=8 March 2015|url-status=live|archive-url=https://web.archive.org/web/20150317061401/http://www.emcdda.europa.eu/publications/drug-profiles/synthetic-cathinones|archive-date=17 March 2015}} Cathinone is structurally related to methcathinone, in much the same way as amphetamine is related to methamphetamine. Cathinone differs from amphetamine by possessing a ketone oxygen atom (C=O) on the β (beta) position of the side chain. Advancements in synthesizing cyclic cathinones based on α-tetralone have employed chiral HPLC-CD techniques to determine the absolute configuration of enantiomers, an approach that may contribute to the development of pharmaceutical analogs with antidepressant potential.{{cite journal | vauthors = Paškan M, Dobšíková K, Kuchař M, Setnička V, Kohout M | title = Synthesis and absolute configuration of cyclic synthetic cathinones derived from α-tetralone | journal = Chirality | volume = 36 | issue = 2 | pages = e23646 | date = February 2024 | pmid = 38353318 | doi = 10.1002/chir.23646 | doi-access = free }} The corresponding substance cathine, is a less powerful stimulant. The biophysiological conversion from cathinone to cathine is to blame for the depotentiation of khat leaves over time. Fresh leaves have a greater ratio of cathinone to cathine than dried ones, therefore having more psychoactive effects.

There are many cathinone derivatives that include the addition of an R group to the amino end of the molecule. Some of these derivatives have medical uses as well. Bupropion is one of the most commonly prescribed antidepressants and its structure is Cathinone with a tertiary butyl group attached to the nitrogen and chlorine attached to the benzene ring meta- to the main carbon chain.

Other cathinone derivatives are strong psychoactive drugs. One such drug is methylone, a drug structurally similar to MDMA.

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• Bupropion
• Central nervous system
• Khat
• Substituted cathinone

{{reflist}}

• [http://www.erowid.org/chemicals/cathinone/ Erowid Cathinone Vault] {{Webarchive|url=https://web.archive.org/web/20080622214102/https://www.erowid.org/chemicals/cathinone/ |date=2008-06-22 }}
• [https://www.theguardian.com/israel/Story/0,2763,1296958,00.html Cathinone Popularity Soars in Israel]

{{Stimulants}}

{{Monoamine releasing agents}}

{{TAAR modulators}}

{{Phenethylamines}}

{{Chemical classes of psychoactive drugs}}

Category:Amphetamine alkaloids

Category:Drugs acting on the cardiovascular system

Category:Euphoriants

Category:Norepinephrine-dopamine releasing agents

Category:Phenyl compounds

Category:Stimulants

Category:TAAR1 agonists